**2.1 Risk factors**

#### *2.1.1 DM duration and poor glycemic control*

Diabetic retinopathy (DR) is a chronic complication associated with long DM duration and poor glycemic control, the overall incidence of DR and of visionthreatening forms of DR (VTDR) being higher in T1DM than in T2DM [8]. The United Kingdom Prospective Diabetes Study (UKPDS) showed that both the incidence and progression of DR correlate with elevated HbA1c, emphasizing the importance of good glycemic control to prevent visual impairment [9]. Every 1% decrease in HbA1c leads to a 40% reduction in the risk of developing retinopathy, a 25% reduction in the risk of progression to vision-threatening retinopathy, and a 15% reduction in the risk of blindness [10].

#### *2.1.2 Arterial hypertension*

The correlations between cardiovascular risk factors and the occurrence and evolution of DR are still a subject of study. However, there is clear evidence that the processes of arteriolosclerosis and the mechanical trauma to the vascular endothelium caused by elevated systolic and diastolic blood pressure are both cofactors in worsening DR. Some but not all studies have shown a negative impact of high blood pressure on DR [9, 11, 12]. The UKPDS has demonstrated a significant correlation between systolic arterial hypertension and DR incidence in T2DM. Thus, patients with blood pressure (BP) > 140 mmHg have a 2.8 times higher risk of developing DR than those with BP <125 mmHg. In the study of Lurbe et al. [13], in a cumulative exposure model, HbA1c and elevated diastolic BP values are predictive factors for the occurrence and progression of RD. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), diastolic BP emerged as a significant risk factor for DR progression in T1DM, but no correlations were found for systolic BP or T2DM [14, 15]. Therapeutic lowering BP was found to have a protective role on retinal lesions in several studies supporting the recommendations for tight blood pressure control to further prevent visual loss n T2DM [9, 14, 16].

#### *2.1.3 Lipidic disorders and serum LDL*

Unlike glycemic control, the role of serum lipids in DR pathogenesis is less clear. There is no parameter in the lipid profile that is strictly associated with the incidence or progression of DR. However, elevated total cholesterol, LDL-cholesterol, Apo B

**251**

*2.1.5 Pregnancy*

*Microvascular Complications of Diabetes Mellitus: Focus on Diabetic Retinopathy (DR)…*

and Apo B/Apo A ratio are correlated with the appearance of hard exudates, these being lipoprotein extravasations in the retinal capillaries. Hadjadj et al. showed that serum triglyceride levels are correlated with the occurrence of nephropathy and retinopathy in patients with T1DM [17]. Several randomized trials confirmed that the treatment of dyslipidemia can prevent the development of DR [14, 15, 18–21].

Several studies have revealed that in young adults with T1DM, genetic predisposition for the development of DR is connected with the presence of HLA DR3/DR4 antigens. Furthermore, different alleles for codification of cytokines and chemokines, as well as vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)beta1 were characterized, explaining different predisposition for DR in diabetic patients. VEGF plays a key role in increased microvascular permeability and neovascularization in proliferative diabetic retinopathy. The VEGF gene is located on chromosome 6 (6p21.3) and is highly polymorphic in the promoter region, correlated with VEGF expression and activity. In a study by Buranczynska et al., the presence of the D allele at −2549 in the promoter region of the VEGF gene enhanced gene expression [22]. The DD genotype was associated with DR but not with nephropathy, suggesting a cell-specific target of the VEGF isoform. In a study of Jalal and Kalia, regarding the polymorphism of VEGF genes in India, allele A and AA genotype of rs2146323 were significantly correlated both with incidence and with severity of DR [23]. Awata et al. described C (−634) G polymorphism of VEGF gene to be related to macular edema as well as diabetic retinopathy [24]. Ray et al. identified VEGF −460 C genotype to increase VEGF basal promoter activity by 71%, leading to a 2.5 increased risk of proliferative DR [25]. TGF beta signaling is considered to have an immunosuppressive role in the retina. Disorders affecting this pathway lead, at least in experimental animal models, to loss of pericytes, microaneurysms and leakage, finding resembling diabetic retinopathy [26]. Beránek et al. found a more frequent incidence of 915G/C (R25P) polymorphism of TGF beta gene in patients with DR compared to control subjects [27].

Hormonal alterations during pregnancy were found to be an independent risk factor both for onset and for progression of DR, especially PDR, posing many challenges regarding the management of these patients [28–30]. Another mechanism is

Recent studies focus on the significance of inflammation in the developments of DR [32–36]. There is strong evidence that ischemia and retinal hypoxia induce release of VEGF and inflammatory molecules at the level of endothelial and glial cells. Furthermore, several studies support the idea that ocular inflammatory disorders, such as prolonged post cataract surgery healing, uveitis, keratitis, are related

There are increased evidences that chronic systemic inflammation is also related to increased risk of DR onset and progression. In an experimental animal model, recurrent exposure to systemic LPS leads to injury of capillary endothelium and in vivo thinning of the retina in hyperglycemic mice, but not in healthy controls [37]. There are clinical evidences of increased incidence of DR and PDR in long standing non-healing foot ulcer, that could be explained due to the associated

pregnancy-induced hypertension and pre-eclampsia [31].

chronic low-grade systemic inflammation [38–42].

*2.1.6 Ocular and systemic inflammation*

to DR progression [32–36].

*DOI: http://dx.doi.org/10.5772/intechopen.96548*

*2.1.4 Genetic predisposition*

and Apo B/Apo A ratio are correlated with the appearance of hard exudates, these being lipoprotein extravasations in the retinal capillaries. Hadjadj et al. showed that serum triglyceride levels are correlated with the occurrence of nephropathy and retinopathy in patients with T1DM [17]. Several randomized trials confirmed that the treatment of dyslipidemia can prevent the development of DR [14, 15, 18–21].
